CHARACTERIZATION OF SEMAPHORIN IV IN TUMORIGENESIS

Semaphorin IV 在肿瘤发生中的表征

基本信息

批准号：
6514332
负责人：
CHRISTIN TSE
金额：
$ 0.59万
依托单位：
SAGRES DISCOVERY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-02-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/6514332
关键词：
DNA methylation apoptosis athymic mouse azacitidine cell line neoplasm /cancer genetics northern blottings nucleic acid repetitive sequence ovary neoplasms polymerase chain reaction small cell lung cancer tumor suppressor genes tumor suppressor proteins vascular endothelial growth factors western blottings

项目摘要

SEMAPHORIN IV (SEMA IV) resides in 3p21.3 on chromosome 3, a region that exhibits a high loss of heterozygosity in several types of cancers, e.g., small cell lung cancer (SCLC) and ovarian cancer. Recently, the laboratory of Dr. Naylor demonstrated that tumor growth was inhibited in mouse fibrosarcoma (A9) cells transfected with SEMA IV as opposed to control A9 cells where tumors formed in an athymic nude mice assay. Furthermore, SEMA IV confers protection from chemotherapeutic drug-induced apoptosis. Thus, SEMA IV appears to be a putative tumor suppressor gene in 3p21.3. By definition, this would indicate that loss of SEMA IV function would result in tumor growth. Over 90 percent of SCLC have loss a region in chromosome 3 overlapping with the SEMA IV locus, however, no mutations have been found in the remaining locus. Another unexplored possibility by which sema iv may be disrupted is by differential DNA methylation. In neuronal development, Sema IV serves as a chemorepellent protein in axonal guidance, eliciting a response through the neuropilin-2 (np-2) receptor. However, its role in tumorigenesis is unknown. Recently, it has been shown that np-2 as well as, neuropilin-1 (np-1) also serve as coreceptors for vascular endothelial growth factor (VEGF165). VEGF165, one of the most potent angiogenic factors, also binds two receptor tyrosine kinases, KDR and flt-1. Np-1 has been shown to increase the affinity of VEGF165 to KDR and its mitogenic activity. Taken together, one action of SEMA IV in tumor suppression may be to competitively inhibit VEGF action. The goal of this proposal is to determine if DNA methylation is involved in the downregulation of SEMA IV gene expression in SCLC and to elucidate the mechanism(s) by which sema iv suppresses tumor formation.

SEMAPHORIN IV (SEMA IV) 位于 3 号染色体上的 3p21.3，该区域在几种类型的癌症中表现出高度杂合性丢失，例如小细胞肺癌 (SCLC) 和卵巢癌。最近，Naylor 博士的实验室证明，用 SEMA IV 转染的小鼠纤维肉瘤 (A9) 细胞中的肿瘤生长受到抑制，而对照 A9 细胞在无胸腺裸鼠试验中形成肿瘤。此外，SEMA IV 还可防止化疗药物诱导的细胞凋亡。因此，SEMA IV 似乎是 3p21.3 中假定的肿瘤抑制基因。根据定义，这表明 SEMA IV 功能的丧失将导致肿瘤生长。超过 90% 的 SCLC 丢失了 3 号染色体中与 SEMA IV 基因座重叠的区域，但在剩余基因座中未发现突变。另一种尚未探索的 sema iv 可能被破坏的可能性是差异 DNA 甲基化。在神经元发育中，Sema IV 作为轴突引导中的化学排斥蛋白，通过神经毡蛋白-2 (np-2) 受体引发反应。然而，其在肿瘤发生中的作用尚不清楚。最近，研究表明 np-2 以及神经毡蛋白-1 (np-1) 也可作为血管内皮生长因子 (VEGF165) 的辅助受体。 VEGF165 是最有效的血管生成因子之一，还结合两种受体酪氨酸激酶：KDR 和 flt-1。 Np-1 已被证明可以增加 VEGF165 与 KDR 的亲和力及其促有丝分裂活性。总而言之，SEMA IV 抑制肿瘤的作用之一可能是竞争性抑制 VEGF 作用。该提案的目的是确定 DNA 甲基化是否参与 SCLC 中 SEMA IV 基因表达的下调，并阐明 sema iv 抑制肿瘤形成的机制。